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• W3196283453 abstract "HomeRadiologyRecently Published PreviousNext Original ResearchFree AccessBreast ImagingReducing False-Positive Screening MRI Rate in Women with Extremely Dense Breasts Using Prediction Models Based on Data from the DENSE TrialBianca M. den Dekker, Marije F. Bakker, Stéphanie V. de Lange, Wouter B. Veldhuis, Paul J. van Diest, Katya M. Duvivier, Marc B. I. Lobbes, Claudette E. Loo, Ritse M. Mann, Evelyn M. Monninkhof, Jeroen Veltman, Ruud M. Pijnappel, Carla H. van Gils For the DENSE Trial Study Group1Bianca M. den Dekker, Marije F. Bakker, Stéphanie V. de Lange, Wouter B. Veldhuis, Paul J. van Diest, Katya M. Duvivier, Marc B. I. Lobbes, Claudette E. Loo, Ritse M. Mann, Evelyn M. Monninkhof, Jeroen Veltman, Ruud M. Pijnappel, Carla H. van Gils , For the DENSE Trial Study Group1Author AffiliationsFrom the Department of Radiology (B.M.d.D., S.V.d.L., W.B.V., R.M.P.), Julius Center for Health Sciences and Primary Care (M.F.B., S.V.d.L., E.M.M., C.H.v.G.), and Department of Pathology (P.J.v.D.), University Medical Center Utrecht, Utrecht University, PO Box 85500, 3508 GA Utrecht, the Netherlands; Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (K.M.D.); Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, and GROW School for Oncology and Developmental Biology, Maastricht University, and Department of Medical Imaging, Zuyderland Medical Center, Sittard-Geleen, the Netherlands (M.B.I.L.); Department of Radiology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands (C.E.L.); Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands (R.M.M.); Department of Radiology, Ziekenhuisgroep Twente, Almelo, the Netherlands (J.V.); and Dutch Expert Center for Screening, Nijmegen, the Netherlands (R.M.P.).Address correspondence to C.H.v.G. (e-mail: [email protected]).Bianca M. den DekkerMarije F. BakkerStéphanie V. de LangeWouter B. VeldhuisPaul J. van DiestKatya M. DuvivierMarc B. I. LobbesClaudette E. LooRitse M. MannEvelyn M. MonninkhofJeroen VeltmanRuud M. PijnappelCarla H. van Gils For the DENSE Trial Study Group1Published Online:Aug 17 2021https://doi.org/10.1148/radiol.2021210325See editorial byMassimo ImbriacoMoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked InEmail 1 Members of the DENSE trial study group are listed at the end of this article.AbstractBackground High breast density increases breast cancer risk and lowers mammographic sensitivity. Supplemental MRI screening improves cancer detection but increases the number of false-positive screenings. Thus, methods to distinguish true-positive MRI screening results from false-positive ones are needed.Purpose To build prediction models based on clinical characteristics and MRI findings to reduce the rate of false-positive screening MRI findings in women with extremely dense breasts.Materials and Methods Clinical characteristics and MRI findings in Dutch breast cancer screening participants (age range, 50–75 years) with positive first-round MRI screening results (Breast Imaging Reporting and Data System 3, 4, or 5) after a normal screening mammography with extremely dense breasts (Volpara density category 4) were prospectively collected within the randomized controlled Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial from December 2011 through November 2015. In this secondary analysis, prediction models were built using multivariable logistic regression analysis to distinguish true-positive MRI screening findings from false-positive ones.Results Among 454 women (median age, 52 years; interquartile range, 50–57 years) with a positive MRI result in a first supplemental MRI screening round, 79 were diagnosed with breast cancer (true-positive findings), and 375 had false-positive MRI results. The full prediction model (area under the receiver operating characteristics curve [AUC], 0.88; 95% CI: 0.84, 0.92), based on all collected clinical characteristics and MRI findings, could have prevented 45.5% (95% CI: 39.6, 51.5) of false-positive recalls and 21.3% (95% CI: 15.7, 28.3) of benign biopsies without missing any cancers. The model solely based on readily available MRI findings and age had a comparable performance (AUC, 0.84; 95% CI: 0.79, 0.88; P = .15) and could have prevented 35.5% (95% CI: 30.4, 41.1) of false-positive MRI screening results and 13.0% (95% CI: 8.8, 18.6) of benign biopsies.Conclusion Prediction models based on clinical characteristics and MRI findings may be useful to reduce the false-positive first-round screening MRI rate and benign biopsy rate in women with extremely dense breasts.Clinical trial registration no. NCT01315015© RSNA, 2021Online supplemental material is available for this article.See also the editorial by Imbriaco in this issue.Download as PowerPointSummaryPrediction models based on clinical characteristics and MRI findings may be useful to reduce the false-positive rate of first-round supplemental screening MRI in women with extremely dense breasts.Key Results■ Using prospectively collected data of 454 women from the Dense Tissue and Early Breast Neoplasm Screening trial, a prediction model based on clinical characteristics and MRI findings (area under the receiver operating characteristics curve [AUC], 0.88) could prevent 45.5% of false-positive recalls and 21.3% of benign biopsies after first-round supplemental MRI screening in women with extremely dense breast tissue without missing any cancers.■ A model using data from MRI findings plus age (AUC, 0.84) could help prevent 35.5% of false-positive recalls and 13.0% of benign biopsies without missing any cancers.IntroductionPopulation-based mammographic screening has proven effective in terms of mortality reduction due to breast cancer detection and treatment at an early stage (1,2). However, in women with high breast density, the sensitivity of mammography is markedly reduced because of the masking effect of the fibroglandular tissue (3–6). This is particularly important, as the breast cancer risk in women with extremely dense breasts is twice as high as that in women with average breast density (7).MRI is the most sensitive technique with which to screen women at high risk (8–14). More recently, MRI has also been considered as a screening tool in women at average risk with dense breasts (15–19). The Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial was designed to evaluate the effectiveness of screening with mammography and MRI compared with mammography alone in Dutch breast cancer screening participants (age range, 50–75 years) with extremely dense breasts (20). A significant difference in interval cancers was found in the intention-to-screen analysis: the rate was 5.0 of 1000 screenings in the mammography-alone group versus 2.5 of 1000 screenings in the group invited for supplemental MRI (P < .001). This rate in the MRI-invitation group consisted of an interval cancer rate of 0.8 of 1000 screenings in the women who underwent MRI (59% of invited women) and 4.9 of 1000 in those who did not accept the MRI invitation. This study therefore provided strong evidence that supplemental MRI screening in women with extremely dense breasts improves detection of clinically relevant cancers (21). In contrast with its high sensitivity, the moderate specificity of breast MRI can result in false-positive findings that necessitate further imaging, tissue sampling, or additional follow-up examinations (16–18,21) (Fig 1). The recall rate among first-round DENSE participants was 94.9 of 1000 screenings, with a false-positive rate (FPR) of 79.8 of 1000. Other supplemental screening MRI studies have reported similar FPRs ranging from 52 of 1000 to 97 of 1000 (16,18). Recall and the subsequent diagnostic work-up often are associated with patient anxiety, increased health care costs, and sometimes biopsy-related morbidity (22–24). High recall rates may complicate implementation of supplemental MRI screening on a large scale, as sufficient capacity for timely diagnostic work-up is required. Reduction of the FPR is an important issue when considering the use of breast MRI as a screening tool (25). Therefore, the purpose of this study was to explore the potential of prediction models, based on clinical characteristics and MRI findings, to reduce the FPR.Figure 1: Example of a false-positive MRI. In a 59-year-old participant, first-round screening MRI showed an 8-mm irregular mass in the right breast. The lesion shows rapid heterogeneous type 2 enhancement, low T2 signal intensity, and no evident diffusion restriction. Histopathologic findings showed sclerotic stroma and apocrine metaplasia.Figure 1:Download as PowerPointOpen in Image Viewer Materials and MethodsStudy SampleThe DENSE trial design was reported elsewhere (20,21). The study protocol is available through ClinicalTrials.gov (NCT01315015). DENSE is a multicenter randomized controlled trial that evaluates the effect of supplemental MRI screening in women with extremely dense breasts. Participants in the biennial Dutch population–based screening program (aged 50–75 years) with negative mammographic findings and extremely dense breasts (Volpara density category 4) were eligible for randomization. A total of 40 373 women were randomized for supplemental MRI screening for three consecutive rounds (intervention arm) or mammographic screening only (control arm). Results regarding the primary outcome, the difference in interval cancer rate during a 2-year screening period, were reported elsewhere (21) as well as studies focusing on other research questions (26–29). Ethical approval for the DENSE trial was obtained from the Dutch Minister of Health, Welfare, and Sport on November 11, 2011 (2011/19 WBO, the Hague, the Netherlands). All study participants provided written informed consent.From December 2011 to November 2015, 4783 DENSE participants underwent first-round screening MRI. In our present analysis, all 454 participants recalled for diagnostic work-up after a Breast Imaging Reporting and Data System (BI-RADS) category 3, 4, or 5 result were included (Fig 2). Study data are available from the corresponding author on reasonable request.Figure 2: Flowchart shows enrollment in the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial and selection of participants for the present analysis. Breast cancer screening participants (aged 50–75 years) with extremely dense breast tissue were assigned in a 1:4 ratio to a group that was invited to undergo supplemental MRI screening or to a group that underwent mammographic screening only. Approximately 59% of the participants in the MRI-invitation group actually underwent MRI. A total of 454 participants had a positive MRI screening result and constituted the study sample for the present analysis (dashed box).Figure 2:Download as PowerPointOpen in Image Viewer Clinical Characteristics and MRI FindingsAll participants were asked to complete a questionnaire on health status and breast cancer risk factors at the time of recruitment, including personal and family history of breast cancer, age at menarche, parity, age at first live birth, breastfeeding status, body mass index, hormone use after age 50 years (hormonal replacement therapy and contraceptive use), and menopausal status.MRI ProtocolAll participants underwent 3.0-T MRI (Philips Achieva or Siemens Ingenia) using a dedicated phased-array bilateral breast coil. The full MRI protocol is described in detail elsewhere (21). A gadolinium-based contrast agent (Gadovist, Bayer) was injected (1 mL/sec) for a total dose of 0.1 mmol per kilogram of body weight.Image AnalysisMRI scans were read by dedicated breast radiologists (including, among others, W.B.V., R.M.P., R.M.M., M.B.I.L., K.M.D., and J.V.) with 8.5 to more than 25 years of experience reading breast MRI scans. MRI scans were classified according to the BI-RADS MRI lexicon (fourth edition). Readers had access and were not blinded to current or previous breast imaging findings in accordance with clinical and screening practice. In our present analysis, all participants with a BI-RADS 3, 4, or 5 finding were included. In case of a BI-RADS 3 finding, independent double reading was performed by a second breast radiologist from the same reader group mentioned previously, and discrepancies were resolved by consensus. In case of a final BI-RADS 3 finding, MRI was repeated after 6 months. In case of a BI-RADS 4 or 5 finding, histologic sampling was indicated.Prospectively collected MRI variables included BI-RADS classification, background parenchymal enhancement, symmetry of enhancement, lesion location, size, type, enhancement kinetics, shape, margin, distribution, and internal enhancement characteristics. In case of multiple lesions, the BI-RADS descriptors of the most suspicious lesion (based on the highest BI-RADS classification) were used for analysis.Breast cancer diagnosis was defined as a histopathologic result of ductal carcinoma in situ or invasive carcinoma at histologic sampling or surgery; any other histopathologic result was considered a benign finding.Statistical AnalysisData were analyzed by using SPSS software (version 25, IBM) and RStudio software (version 3.6.1, RStudio). Clinical characteristics and MRI findings were summarized using descriptive statistics, and differences between true-positive and false-positive results were tested using the two-sample t test, Wilcoxon rank sum test, Pearson χ2 test, or Fisher exact test. P values less than .05 were considered indicative of a significant difference.Multivariable logistic regression models were built, starting with a full model including all clinical characteristics and MRI findings. For the second model, backward elimination was used to remove variables. Akaike Information Criterion was used to compare models, with the preferred model being the one with the minimum Akaike Information Criterion value. Akaike Information Criterion rewards the goodness of fit of the model but penalizes increasing numbers of variables, resulting in a value that reflects the trade-off between goodness of fit and simplicity of the model (30). A third model, based on age and MRI findings only, was built to evaluate the potential of a model based solely on readily available data. Areas under the receiver operating characteristic curve (AUCs) and calibration plots were obtained. Internal validation was performed using 200 bootstrap samples to obtain optimism-corrected estimates (31). In the receiver operating characteristic curves of all models, the cutoff point where sensitivity falls below 100% was identified to calculate the maximum number of false-positive MRI screenings that could be identified with the model without missing any breast cancers.Strategy of Not Recalling Women with BI-RADS 3 ResultsIn the DENSE trial, women with a final BI-RADS 3 result were scheduled for repeat MRI after 6 months. However, a simple and easy-to-implement strategy to reduce FPR could be to not recall women with a BI-RADS 3 result at all. This theoretical strategy was compared with the performance of the prediction models.ResultsClinical Characteristics and MRI FindingsAmong 40 373 women in the DENSE trial, 454 (median age, 52 years; interquartile range, 50–57 years) had positive results at MRI screening (Fig 2). A total of 79 participants (median age, 54 years; interquartile range, 51–61 years) were diagnosed with breast cancer (true-positive findings) and 375 (median age, 52 years; interquartile range, 50–56 years) had false-positive MRI findings (Table 1). A total of 432 women (95.2%) completed the questionnaire on health status and breast cancer risk factors. Most were postmenopausal, were 13 years old at menarche (mean age, 13.4 years ± 1.4 [standard deviation]), had a healthy weight (mean body mass index, 22.1 kg/m2 ± 2.8), had given birth two or more times, had zero first-degree relatives with breast cancer, had never used hormones after age 50 years, and had no history of breast biopsy. Median Volpara breast density was 18.8% (interquartile range, 16.7%–22.0%). Among the 454 recalled participants, 150 had BI-RADS 3 lesions (33%), 286 had BI-RADS 4 lesions (63%), and 18 had BI-RADS 5 lesions (4%) (Table 2). Most women had symmetric minimal background parenchymal enhancement. Lesions detected were predominantly masses, and half were smaller than 1 cm (median size, 1.0 cm; interquartile range 0.7–1.0 cm). Most lesions showed rapid initial uptake followed by washout in the delayed phase (type 3 enhancement curve). Of the 279 mass lesions detected, most had an irregular shape, irregular margin, and a heterogeneous internal enhancement pattern (Table E1 [online]). Of the 143 nonmass enhancement lesions detected, most had a focal distribution and heterogeneous internal enhancement pattern (Table E2 [online]). A total of 300 women underwent biopsy—276 after a BI-RADS 4 or 5 lesion was seen at screening MRI and 24 after a BI-RADS 4 or 5 lesion was seen at 6-month follow-up MRI after an initial BI-RADS 3 finding on screening MRI. There were 31 women with an indication for biopsy who did not undergo the procedure because the lesion was no longer visible at additional imaging (n = 18), the lesion was an intramammary lymph node or cyst (n = 8), biopsy of the lesion was technically impossible (n = 2), or the lesion was already histologically proven benign in the past (n = 3). A total of 79 women were diagnosed with breast cancer, of whom 64 had invasive carcinoma and 15 had ductal carcinoma in situ. Women with a breast cancer diagnosis, and thus a true-positive MRI screening examination, were older, had a higher body mass index, and more often had two or more first-degree relatives with breast cancer compared with women with a false-positive screening MRI result (Table 1). MRI findings associated with a true-positive screening MRI result were a higher BI-RADS classification (P < .001), a mass lesion type (P = .02), rapid initial contrast material uptake (P = .01), and wash-out kinetics (P < .001) (Table 2). For the 279 mass lesions seen at screening MRI, an irregular shape (P < .001) and an irregular or spiculated margin (P < .001) were associated with breast cancer diagnosis and thus a true-positive MRI screening result (Table E1 [online]).Table 1: Clinical Characteristics of Breast Cancer Screening Participants with a Positive First-Round Supplemental MRI Screening Result after Normal Mammographic ScreeningTable 2: MRI Findings of Breast Cancer Screening Participants with a Positive First-Round Supplemental MRI Screening Result after Normal Mammographic ScreeningPrediction ModelsThe full model (model A) (Table 3), including all clinical characteristics and MRI findings, based on 328 participants with complete data regarding these variables, yielded an AUC of 0.88 (95% CI: 0.84, 0.92) (Fig 3). The optimism-corrected AUC was 0.80. Among these 328 participants, 64 had breast cancer and 264 had false-positive findings. With the full prediction model, a total of 120 of 264 (45.5%, 95% CI: 39.6, 51.5) false-positive findings could have been identified as false-positive cases without missing any cancers. Among the participants identified as having false-positive findings were 35 of 164 (21%, 95% CI: 16, 28) who underwent biopsy for a benign lesion. Backward selection resulted in a reduced prediction model (model B, Table 3) with the optimal trade-off between goodness of fit and simplicity of the model. The reduced model included the variables age (odds ratio [OR], 1.14; 95% CI: 1.05, 1.24), menopausal status (perimenopausal vs postmenopausal OR, 4.1; 95% CI: 1.7, 10.8), number of first-degree relatives with breast cancer (two or more relatives vs zero relatives: OR, 11; 95% CI: 1, 250), history of breast biopsy (OR, 2.5; 95% CI: 1.1, 5.3), MRI BI-RADS classification (BI-RADS 4 vs BI-RADS 3: OR, 33; 95% CI: 7, 590; BI-RADS 5 vs BI-RADS 3: OR, 710; 95% CI: 83, 17 724), and initial phase kinetics (rapid vs slow: OR, 6.9; 95% CI: 1.4, 63.7). The AUC of the reduced prediction model was 0.85 (95% CI: 0.80, 0.90) (Fig 3). The optimism-corrected AUC was 0.82. With the reduced prediction model, a total of 85 of 264 (32.2%; 95% CI: 26.8, 38.1) false-positive MRI screenings could have been identified without missing any cancers. Among the identified false-positive findings were 17 of 164 (10.4%; 95% CI: 6.5, 16.1) participants who underwent biopsy for a benign lesion. A third model (model C, Table 3), including all MRI findings as presented in Table 2 plus age, based on 369 participants for whom data were complete, yielded a comparable performance with AUC of 0.84 ([95% CI: 0.79, 0.88] versus full-model AUC of 0.88; P = .15) (Fig 3). The optimism-corrected AUC was 0.78. Among these 369 participants, 68 had breast cancer and 301 had false-positive findings. With the MRI plus age model, 107 of 301 (35.5%; 95% CI: 30.4, 41.1) false-positive MRI screenings could have been identified as false-positive without missing any cancers. Among the identified false-positive cases were 24 of 185 (13%, 95% CI: 9, 19) participants who underwent biopsy for a benign lesion.Table 3: Results of Multivariable Logistic Regression Analysis Showing Odds Ratios for True-Positive MRI ScreeningFigure 3: Graph shows areas under the receiver operating characteristic curves (AUCs) of three prediction models for true-positive MRI screening. Model A (green): The full model, including all clinical characteristics and MRI findings, as presented in Tables 1 and 2, based on 328 participants. Model B (blue): The reduced model, including the variables age, menopausal status, number of first-degree relatives with breast cancer, history of breast biopsy, MRI Breast Imaging Reporting and Data System classification, and initial phase kinetics. Model C (purple): The model based on readily available data, including all MRI findings, as presented in Table 2 plus age, based on 369 participants.Figure 3:Download as PowerPointOpen in Image Viewer Strategy of Not Recalling Women with BI-RADS 3 FindingsNot recalling women with a BI-RADS 3 finding at supplemental screening MRI (n = 150) would reduce the recall rate by 33% (from 94.9 of 1000 to 63.6 of 1000) and the FPR by 39.0% (from 79.8 of 1000 to 48.7 of 1000) at the cost of missing four breast cancers. These cases included one invasive lobular carcinoma (Bloom and Richardson grade 2) in a 62-year-old woman, one papillary carcinoma with ductal carcinoma in situ in a 50-year-old woman, one ductal carcinoma in situ (grade unknown) in a 71-year-old woman, and one triple-negative invasive carcinoma (grade 3) in a 52-year-old woman. The triple-negative cancer was in fact not visible at screening MRI but was identified as a new lesion at 6-month follow-up MRI performed for a BI-RADS 3 lesion in the contralateral breast. Therefore, realistically, three cancers would have been missed if all 150 participants with a BI-RADS 3 screening MRI result were not recalled. This is in line with the no more than 2% likelihood of a malignant neoplasm for a BI-RADS 3 score (32).DiscussionPrediction models based on clinical characteristics and MRI findings may enable identification of a substantial part of false-positive first-round supplemental MRI screenings, reducing false-positive rate and benign biopsy rate without missing any cancers. The full model (area under the receiver operating characteristics curve [AUC], 0.88; 95% CI: 0.84, 0.92), based on all clinical characteristics and MRI" @default.
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• W3196283453 title "Reducing False-Positive Screening MRI Rate in Women with Extremely Dense Breasts Using Prediction Models Based on Data from the DENSE Trial" @default.
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